The present invention relates to novel phosphonates which can be employed as precursors to a variety of biologically-active materials; including 13-cis retinoic acid (accutane), retin-A and beta carotene. The phosphonates of the present invention can be synthesized by the reaction of a cyclohexenyl-group-containing C-14 through C-16 aldehyde, such as 2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butenal, with a phosphonic acid ester, such as methylenebisphosphonic acid, tetraethyl ester.
A procedure for producing vitamin A acetate from beta-ionone has been described by Reif and Grassner [Chemie-Ing. Techn., 45, 646-652 (1973)]: ##STR2##
Similarly, Pommer and Kuhn [Angew.Chem., 72, 911 (1960)] have described a procedure for preparing beta-carotene from the same beta-ionone-derived triphenylphosphonium salt: ##STR3## formed in the course of the Reif et al., synthesis. The disadvantages of these procedures include the fact that the triphenylphosphine reactant required for the syntheses is relatively expensive and that the byproduct of the reactions, pH.sub.3 PO, is not water soluble, thus making it difficult to isolate the desired product.
Surmatis and Thommen have described a process for preparing beta-carotene utilizing a phosphonate in a Wittig-type reaction [J. Org. Chem., 34, 559 (1969)]. As essential step of this procedure involves the reaction of a C-20 dibromo compound with a trialkyl phosphite: ##STR4##
Although the C-20 dibromo compound of Surmatis et al. can be reacted with trialkyl phosphites, the literature does not report similar reactions for structurally related C-15 halides. Indeed, the literature shows that the compound 1-bromo-3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadiene ##STR5## is not stable at room temperature. (Bull. Soc. Chim. Fr., Part II, 746-750 (1973)].
Other procedures for preparing retinoid intermediates and beta-carotene are shown in the prior art, e.g., Babler U.S. Pat. No. 4,175,204; F. Frickel, "The Retinoids", edited by M. B. Sporn, A. B. Roberts and D. S. Goodman, Academic Press (Orlando, Fla., 1984), pp. 77-145; and R. S. H. Liu and A. E. Asato, Tetrahedron, 40, 1931-1969 (1984).